Tetrahydroquinoline phenoxyacetic acid derivatives

ABSTRACT

COMPOUND OF THE FORMULA   1-(R1-OOC-C(-CH3)2-O-),4-R3,R2-BENZENE   WHEREIN R1 IS H OR ALKYL OF 1-10 CARBON ATOMS; R2 IS H, ALKYL OF 1-4 CARBON ATOMS OR HALOGEN; AND R3 IS PYRROLIDINO, PIPERIDINO, 3-HYDROXYPYRROLIDINO, 3-HYDROXYPIPERIDINO, ISOINDOLINO OPTIONALLY SUBSTITUTED IN THE AROMATIC RING BY ONE OR MORE ALKYL, ALKOXY GROUPS AND HALOGEN OR BY A METHYLENEDIOXY GROUP, 1,2,3,4-TETRAHYDROQUINOLINO, 1,2,3, 4-TETRAHYDRO-4-QUINOLYL, 1-ALKYL-1,2,3,4-TETRAHYDRO-4-QUINOLYL, 1-BENZIMIDAZOLYL,, 2-ALKYL-1-BENZIMIDAZOLYL, 1-PYRRYL, 1-BENZOTRIAZOLYL, 2-INDANYL OR 4-PIPERIDINOPHENYL, ALKYL AND ALKOXY IN EACH INSTANCE CONTAINING 1-4 CARBON ATOMS, AND SALTS THEREOF, POSSESS CHLOROESTEROL AND TRIGLYCERIDE BLOOD SERUM LEVEL-LOWERING AND ENZYME-INDUCING ACTIVITY.

United States Patent 3,804,839 TETRAHYDROQUINOLINE PHENOXYACETIC ACIDDERIVATIVES Johann Dahm, Joachim Borck, Herbert Nowak, Zdenek Simane,and Detlev Kayser, Darmstadt, Germany, assignors to Merck PatentGesellschaft mit beschrankter Haftung, Darmstadt, Germany No Drawing.Filed Mar. 13, 1972, Ser. No. 234,343 Claims priority, applicationGermany, Mar. 15, 1971, P 21 12 272.5 Int. Cl. C07d 33/48 US. Cl.260-287 R 6 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formulawherein R is H or alkyl of 1-10 carbon atoms; R is H, alkyl of 1-4carbon atoms or halogen; and R is pyrrolidino, piperidino,3-hydroxypyrrolidino, 3-hydroxypiperidino, isoindolino optionallysubstituted in the aromatic ring by one or more alkyl, alkoxy groups andhalogen or by a methylenedioxy group, 1,2,3,4-tetrahydroquinolino,1,2,3, 4-tetrahydro-4-quinolyl, 1alkyl-1,2,3,4-tetrahydro-4-quinolyl,l-benzimidazolyL, 2-alkyl-l-benzimidazolyl, l-pyrryl, l-benzotriazolyl,Z-indanyl or 4-piperidinophenyl, alkyl and alkoxy in each instancecontaining 1-4 carbon atoms, and salts thereof, possess chloresterol andtriglyceride blood serum level-lowering and enzyme-inducing activity.

BACKGROUND OF THE INVENTION This invention relates to novelphenoxyacetic acids and esters thereof.

SUMMARY OF THE INVENTION The novel 4-substituted phenoxy-acetic acidsand esters thereof of this invention have the general formula I whereinR is H or alkyl of 1-10 carbon atoms; R is H, alkyl of 1-4 carbon atomsor halogen, i.e., F, Cl, Br or I; R is pyrrolidino, piperidino,3-hydroxypyrrolidino, 3- hydroxypiperidino, isoindolino optionallysubstituted in the aromatic ring by one or more of alkyl, alkoxy andhalogen or by a methylenedioxy group; 1,2,3,4-tetrahydroquinolino,1,2,3,4-tetrahydro-4-quinolyl, 1-alkyl-1,2,3,4-tetrahydro-4-quinolyl,l-benzimidazolyl, 2-alky1-1-benzimidazolyl, l-pyrryl, l-benzotriazolyl,Z-indanyl or 4-piperidinophenyl, alkyl and alkoxy in each instancecontaining 1-4 carbon atoms; and the physiologically acceptable saltsthereof with acids or bases. These compounds possess, with goodcompatibility, excellent cholesterol and triglyceride blood serumlevel-lowering and enzyme-inducing activities. They can therefore beemployed as drugs and also as intermediate products for the preparationof other drugs.

Particularly preferred are those compounds of the Formula I wherein Rcontains at least one nitrogen atom.

DETAILED DISCUSSION Of the compounds of this invention, preferred arethose of Formulae Ia through Ih, wherein R is H or alkyl of 1-4 carbonatoms and R; has the value given above:

3,804,839 Patented Apr. 16, 1974 wherein R is H or OH and n is 1 or 2;

wherein the aromatic ring of the isoindolino group is unsubstituted oroptionally substituted by one or more of wherein Q is CH, C-alkyl inwhich alkyl is of 1-4 carbon atoms or N;

wherein R and R have the values given above, with a compound of theformula XC(CH -COOR (III) wherein X is an optionally esterified OH, Cl,Br or I, and R has the values given above, or with a haloform andacetone in the presence of a condensation agent; or

(b) A compound of Formula IV wherein Y is .tetramethylene,pentamethylene, 2-hydroxytetramethylene, Z-hydroxypentamethylene, oro-xylylene optionally substituted in the aromatic ring by one or more ofalkyl, alkoxy and halogen, or by a methylenedioxy group, Z is Cl, Br, I,NH or an optionally esterified or etherified OH-group, and R and R havethe values given above, is treated with cyclizing agents; or

(c) A compound of Formula V wherein W is an optionally functionallymodified COOH group, and R and R have the values given above, is treatedwith a solvolyzing, thermolyzing, or ester-forming agent, therebyconverting W into the group COOR and optionally a thus-produced compoundof Formula I is converted, by treatment with an acid or base, into aphysiologically acceptable acid addition, metallic or ammonium saltthereof, and/or a compound of Formula I in free base form is liberatedfrom one of the salts thereof by treatment with a base or an acid,respectively.

In the above formulae, R preferably is H or alkyl of 1-4 carbon atoms,in particular methyl or ethyl, and also n-propyl, isopropyl, n-butyl,isobutyl, sec.-butyl and tert.- 'butyl. When R is alkyl of up to carbonatoms, it can also be, e.g., n-pentyl, isopentyl, n-hexyl, n-heptyl,n-octyl, isoctyl (Z-ethylhexyl), n-nonyl and n-decyl.

R preferably is H, or, alternatively, CH or Cl. R can also be ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,fluorine, bromine or iodine.

When R contains an alkyl group, methyl is preferred; of the alkoxygroups, methoxy is preferred; and of the alkoxy groups, methoxy ispreferred; and of the halogen atoms, chlorine is preferred.

X and Z preferably are C1 or Br but can also be, e.g., free OH and Iand, additionally, for example, alkyl-sulfonyloxy, preferably of 1-6carbon atoms, e.g., methanesulfonyloxy, arylsulfonyloxy, preferably of6-10 carbon atoms, e.g., benzenesulfonyloxy, p-toluenesulfonyloxy and 1-or 2-naphthalenesulfonyloxy, or acyloxy, preferably alkanoyloxy oraroyloxy of 1-7 carbon atoms, e.g., acetoxy and benzoyloxy; Z can alsobe NH or, for example, an etherified OH-group of preferably 1-7 carbonatoms, e.g., methoxy, benzyloxy.

The compounds of Formula I are preferably obtained by reacting thephenols II with the isobutyric acid derivatives of Formula III. Some ofthe phenols II are known. Those which are novel can be produced inaccordance with conventional methods, for example by splitting themethyl ethers thereof (compounds otherwise corresponding to II, havingan OCH instead of a OH group) with HBr. The Compounds III are for themost part known. The reaction of II with III can be effected by methodsdescribed in the literature. For example, the phenol II can first beconverted into a salt, particularly a metallic salt, for example, analkali metal salt, e.g., a lithium, sodium, or potassium salt.

The salt formation can be achieved, for example, by reacting the phenolwith a reagent producing metallic salts, such as an alkali metal, e.g.,Na; an alkali metal hydride or amide, e.g., LiH and NaH, NaNH and KNH alower alkali metal alcoholate, e.g., lithium, sodium and potassiummethylate, ethylate and tert.-butylate; an organometallic compoundderived from a hydrocarbon, e.g., butyl-lithium, phenyllithium andphenylsodium; a metal hydroxide, carbonate or bicarbonate, e.g., LiOH,NaOH, KOH, Li2CO3, Na CO K2CO3, NaHCO and KHCO The preparation of thesalt of II is advantageously conducted in the presence of a solventselected on the basis of its physicochemical properties, e.g., thesolubility of the starting material or the reactivity of the metalliccompound. Suitable solvents are, e.g., hydrocarbons, including hexane,benzene, toluene and xylene, ethers, including diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane and diethylene glycoldimethyl ether, amides, including dimethylformamide, alcohols, includingmethanol and ethanol, ketones, including acetone and butanone andmixtures thereof.

The phenol II or preferably a salt thereof is reacted with a compound ofFormula HI, preferably in the presence of a diluent, for example, thesolvent utilized for the preparation of the salt, another solvent or thesame solvent diluted with another solvent. The reaction is normallyconducted at a temperature between -20 and 150 0, preferably between 20and C., particularly advantageously at the boiling temperature of thesolvent. This reaction can be effected under an inert gas atmosphere,for example, nitrogen. However, the presence of such an inert gas is notrequired.

The formation of the metallic salt of the phenol II can also beconducted in situ. In this case, the phenol and Compound HI are reactedwith each other in the presence of a salt-forming reagent or anothersuitable base.

In a particularly preferred method Compounds II and III (X=Cl or Br, R=CH or C H are refluxed for several hours together with an alcoholic,e.g., ethanolic, sodium alcoholate solution.

It is also possible to react a free phenol II with a hydroxy acidderivative of Formula III (X=OH), Preferably in the presence of acondensation agent. Suitable condensation agents are, for example,acidic dehydration catalysts, e.g., mineral acids, including sulfuricacid or phosphoric acid, also p-toluenesulfonyl chloride, arsenic acid,boric acid, NaHSO and KHSO disubstituted carbonic acid esters, e.g.,diaryl carbonates, including diphenyl carbonate or, in particular,dialkyl carbonates, dimethyl or diethyl carbonate and carbodiimides,e.g., dicyclohexyl carbodiimide. In case an acid is employed as thecondensation agent, the reaction is suitably conducted in an excess ofthis acid, without the addition of further solvent, at temperatures ofbetween 0 and 100 0, preferably between 50 and 60 C. However, it is alsopossible to add a diluent, e.g., benzene, toluene or dioxane. In case ofa carbonate, the procedure is preferably effected at an elevatedtemperature, suitably from 100 to about 210 C., particularly between 180and 200 C. In this connection, an interesterification catalyst canoptionally be added, e.g., sodium or potassium carbonate or analcoholate, e.g., sodium methylate.

Instead of reaction with Compound III, the phenol II can also be reactedwith a haloform, preferably chloro form or bromoform, and acetone in thepresence of a condensation agent. Especially suitable as thecondensation agent is a strong base, e.g., an alkali metal hydroxide,including NaOH and KOH, preferably utilized in the solid phase. Thisreaction is advantageously conducted in the presence of a diluent, forexample, in the presence of an excess of acetone and/or chloroform. Thereaction is suitably effected at temperatures of between 20 and C.,preferably at the boiling temperature and if necessary, in a sealedvessel, e.g., an autoclave, and/or under an inert gas atmosphere, e.g.,nitrogen. The reaction times range generally between 3 and 40 hours.

Compounds of Formula IV can be cyclized to compounds of Formula I inaccordance with methods described in the literature, e.g., by heating inthe presence or absence of a solvent, optionally in the presence of anacidic or basic catalyst.

Compounds of Formula IV can be produced, for example, by reacting acompound of the formula ZY-Z (VI) wherein Y has the values given aboveand the two groups Z which can be identical or different, in addition tothe values given above can also collectively be 0 or NH, with a compoundof the Formula VII.

wherein R and R have the values given above.

Preferred compounds of Formula VI are those with identical Z groups,e.g., l,4-dichloro-, 1,4-dibromoand 1,4-diiodobutane; 1,5-dichloro-,1,5-dibromoand 1,5-diiodopentane; 1,4-dichloro-, 1,4-dibromoand1,4-diiodo- Z- butanol; 1,5-dichloro-, 1,5-dibromoand 1,5-diiodo-2-pentanol; o-xylylene chloride, bromide and iodide, ophthalyl alcohol(o-hydroxymethylbenzyl alcohol) and the reactive esters thereof, e.g.,the bis-(methanesulfonate) and bis-(p-toluenesulfonate);o-xylylenediamine; phthalan (isocoumaran); isoindoline; and thederivatives of the aryl compounds substituted as indicated above in thearomatic ring, e.g., S-methyl-l-xylylene bromide, 5,6-dimethoxy-l,2-xylylene bromide and 5,6-methylenedioxy- 1,2-xylylenebromide.

Suitable solvents for the cyclization of IV are, for example, water;lower aliphatic alcohols, e.g., methanol, ethanol, isopropanol andn-butanol; glycols, e.g., ethylene glycol, ethers, e.g., diethyl anddiisopropyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons,e.g., petroleum ether and hexane; aromatic hydrocarbons, e.g., benzene,toluene and xylene; halogenated hydrocarbons, e.g., chloroform andchlorobenzene; nitriles, e.g., acetonitrile; amides, e.g.,dimethylformamide and dimethylacetamide; sulfoxides, e.g., dimethylsulfoxide and mixtures of these solvents. Normally, the cyclization isconducted at a temperature of between and 300 0., preferably betweenroom temperature and the boiling temperature of the solvent employed,which latter temperature can be optionally increased by the use ofpressure, e.g., up to 200 atmospheres. The selection of the catalyst isdependent on the type of compound HZ to be split 01?. In case Z=halogen,basic catalysts are preferred, e.g., inorganic bases, including alkalimetal or alkaline earth metal hydroxides, carbonates, and alcoholates,e.g., NaOH, KOH, LiOH, Ba(OH) Ca(*OH) Na CO K2CO3, Ligcog, NaOCH KOCHNaOC H KOC H and K-tert-butylate and organic bases, e.g., tertiarybases, including triethylamine, pyridine, picolines, quinoline. Incontrast thereto, when Z=OH, alkoxy, acyloxy, alkylor arylsulfonyloxy,acidic catalysts are advantageous, e.g., inorganic acids, includingsulfuric acid, polyphosphoric acid, hydrobromic acid and hydrochloricacid; organic acids, including formic acid, acetic acid, propionic acidand p-toluenesulfonic acid which in excess can likewise serve as thesolvent. Ordinarily, more vigorous conditions are required for thecyclization of these substances. Compounds of Formula IV (Z=NI-I splitoif ammonia during heating, for example during melting, thus producingthe desired compounds of-Formula I.

A preferred mode of operation is to produce the compounds of Formula IVin the nascent state (for example, from VI and VII) in the presence orabsence of an additional solvent and, rather than isolating thesecompounds, cyclize them directly to compounds of Formula I. A catalyst,e.g., a base, including NaOH, KOH, sodium carbonate and potassiumcarbonate, can be employed but is not absolutely necessary. It is alsopossible to utilize an excess of the amino compound VII in place of thebase.

Especially advantageous is the reaction of compounds of Formula VIwherein both Z=Br with VII in a boiling alcohol and in the presence ofpotassium carbonate, to produce compounds of Formula IV (X=Br) asintermediates which are cyclized in situ. Under these conditions, thereaction is terminated after about 1-12 hours.

Optionally, unreacted primary amino compounds, (Formula VI) and/orsecondary amino compounds (Formula IV) can be converted, prior to thefurther Working-up procedure, into non-basic compounds by acylation,e.g., by treatment with acetic anhydride.

Compounds of Formula I can also be obtained by sol'volysis, (preferablyhydrolysis), thermolysis, esterfication or interesterification ofcompounds of Formula V wherein W represents, in particular, one of thefollowing residues: COOH; CHal COHal; COOR C(OR COOAcyl, wherein acyl isthe acyl group of a carboxylic acid of up to 25 carbon atoms, preferablyC(NH )=NNH C(NHNH )'=NH; CSOH; COSH; csox CSNH CSNHR or CSNR R wherein Rand R which can be identical or different, in each instance, are alkylor l-4 carbon atoms, preferably methyl or ethyl, or collectivelytetramethylene or pentamethylene, optionally interrupted by 0. Compoundsof Formula V can be produced, for example, by reacting phenols ofFormula II with isobutyric acid derivatives of the formula XC(CH -W.

Hydrolysis of compounds of Formula V wherein W is a functionallymodified COOH-group can be conducted in an acidic or optionally alkalinemedium at temperatures of between '-20 C. and 300 C., preferably at theboiling temperature of the chosen solvent. Suitable acidic catalystsare, for example, hydrochloric, sulfuric, phosphoric and hydrobromicacid. Suitable basic cata lysts include sodium, potassium and calciumhydroxide, and sodium and potassium carbonate. Preferred solvents arewater; lower alcohols, e.g., methanol and ethanol; ethers, e.g.,tetrahydrofuran and dioxane; amides, e.g., dimethylformamide; nitriles,e.g., acetonitrile; sulfones, e.g., tetramethylenesulfone; and mixturesthereof, particularly the mixtures containing water. However, it is alsopossible to saponify the acid derivatives to carboxylic acids of FormulaI wherein R is H, for example, in ether or benzene with the addition ofstrong bases, e.g., potassium carbonate, or without solvents by meltingthe compound with alkalis, e.g., KOH and/or NaOH or alkaline earths.

One embodiment of this invention relates to the saponification ofthioamides (V; W=CSNR R e.g., thiomorpholides, -piperidides,-pyrrolidides, -dimethylamides and -diethylamides. The amides (V; W=CONHare also usable as the starting compounds. The thioamides and/ or amidesare preferably hydrolyzed by heating with aqueous hydrochloric acid. Thestarting thioamides and/ or amides nede not necessarily be isolated inthis process. Instead, the reaction mixture in which they are formed canbe subjected to the hydrolysis.

By the dry heating of, in particular, tertiary alkyl esters of Formula Vwherein W is COO-tert.-alkyl to temperatures of between 50 and 350 C.,acids of Formula I are obtained (R =H). The thermolysis can also beeifected in inert solvents, such as benzene, water, dimethylformamide,ethylene glycol, glycerin, dimethyl sulfoxide and cyclohexanol,preferably with the addition of a catalytic amount of an acid, e.g.,p-toluenesulfonic acid.

An additional embodiment of this invention relates to the hydrolysis ofnitriles of Formula V wherein W is CN. This process can be conducted inan acidic medium, e.g., with acetic acid/HCl, or in an alkaline medium,e.g., with KOH in cyclohexanol.

Esters of the Formula I wherein R =alkyl of up to 10 carbon atoms can beprepared in accordance with methods described in the literature. Thus,it is possible, for example, to react an acid of Formula I (R =H) withthe respective alcohol of the formula R OH wherein R represents alkyl ofup to 10 carbon atoms, in the presence of an inorganic or organic acid,e.g., HCl, HBr, HI, H H PO trifluoroacetic acid, benzenesulfonic acidand p-toluenesulfonic acid, or in the presence of an acidic ionexchanger, optionally in the presence of. an inert solvent, e.g.,benzene, toluene and xylene, at temperatures of between 0 C. andpreferably the boiling temperature of the reaction mixture. The alcoholis preferably utilized in excess. The reaction can be conducted in thepresence of a water-binding agent, e.g., anhydrous heavy metal sulfates,including CuSO Fe (SO.,) NiSO C080,, and ZnSO or in the presence of amolecular sieve. It is also possible to remove the water of reactionazeotropically advantageously by the addition of a hydrocarbon, e.g.,benzene or toluene, or a chlorinated hydrocarbon, e.g., chloroform or1,2-dichloroethane. The esterification takes place under gentleconditions if the water of reaciton is chemically bound by the additionof preferably an equimolar amount of a carbodiimide, e.g.,N,N-dicyclohexyl carbodiimide. In this procedure, inert solvents can beused, e.g., ether, dioxane, benzene or 1,2dimethoxyethane. A base, e.g.,pyridine, can be added. The methyl or ethyl esters can also be producedby reacting the free acids in accordance with methods described in theliterature with diazomethane and diazoethane, respectively, in an inertsolvent, e.g., ether, benzene, or methanol. Esters of Formula I whereinR is alkyl of up to 10 carbon atoms can also be obtained by chemicallyadding the carboxylic acids I (R =H) to an olefin, e.g., isobutylene.This addition reaction is accomplished in accordance with methodsdisclosed in the literature, preferably in the presence of a catalyst,e.g., ZnCl BF H 80 arylsulfonie acids, pyrophosphoric acid, boric acidand oxalic acid, at temperatures of between and 200 C., pressures ofbetween 1 and 300 atmospheres, and in inert solvents, e.g., ether,tetrahydrofuran, dioxane, benzene, toluene and xylene.

Esters of Formula I wherein R is alkyl of up to carbon atoms can also beproduced by reacting a metallic salt of free acid I (R =H), preferablythe alkali metal, lead or silver salt, with an alkyl halogenidecorresponding to the respective alcohol, e.g., those of the formula RHa1, wherein R is alkyl of up to 10 carbon atoms,

optionally in an inert solvent, e.g., ether, benzene and petroleumether, or with an alkyl chlorosulfite, e.g., those of the formula ROSOCI, wherein R is alkyl of up to 10 carbon atoms and by thermolyzingthe thusobtained adducts.

It is also possible to convert the acid halogenides, anhydrides andnitriles of Formula V wherein W is COHal, COOAcyl, or CN into esters ofFormula I wherein R is alkyl of 1-10 carbon atoms, in accordance withthe methods described in the literature, by reaction with an alcohol ofthe formula R OH wherein R is alkyl of up to 10 carbon atoms, if desiredin the presence of an acidic catalyst or a base, e.g., NaOH, KOH, Na COK CO pyridine, or an alkali metal alcoholate corresponding to thealcohol employed. Preferably, an excess of the respective alcohol isutilized, and the procedure is conducted at temperatures of between 0 C.and the boiling temperature of the reaction mixture.

Esters of Formula I wherein R is alkyl of up to 10 carbon atoms can alsobe prepared by reacting other esters of Formula V wherein W is COOR Rbeing any desired organic residue, preferably alkyl of 1-4 carbon atoms,with an excess of the respective alcohol, or by reacting the carboxylicacids I (R =H) with another ester of the respective alcohol, preferablyalkanoates wherein the alkanoyl group contains up to 4 carbon atoms,which are preferably employed in an excess. The reaction is conducted,for example, in accordance with the interesterification methodsdescribed in the literature, especially in the presence of a basic oracidic catalyst, e.g., sodium ethylate and sulfuric acid, attemperatures of between 0 C. and preferably the boiling temperature.

Esters of Formula I wherein R is alkyl of 1-10 carbon atoms can beobtained by solvolyzing compounds of Formula V wherein W is a thioester,iminoether, oximinoether, hydrazone ether, thioamide, amidine, amidoximeor amide hydrazone group, with a dilute aqueous base or acid, e.g.,ammonia, NaOH, KOH, Na CO K CO HCl and H 50 with the addition of therespective alcohol of the formula R OH wherein R is alkyl of up to 10carbon atoms and splitting off hydrogen sulfide, ammonia,

amines, hydrazine derivatives and hydroxylamine, respcctively. Althoughmost of the irninoether hydrochlorides are immediately disassociated inan aqueous solution into the esters and ammonium chlorides at roomtemperature, the solvolysis of other derivatives, e.g., some amidoximesor thioamides, requires temperatures of up to C.

A compound of Formula I having a basic N-atom can be converted with acidinto the corresponding acid addition salt. For this reaction preferredacids are those yielding physiologically acceptable salts. Examples ofsuitable salts are salts of organic and inorganic acids, e.g.,aliphatic, alicyclic, araliphatic, aromatic and heterocyclic monoandpolybasic carboxylic and sulfonic acids, including formic acid, aceticacid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamicacid, benzoic acid, salicyclic acid, phenylpropionic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, ptoluenesulfonic acid, naphthalene-monoand disulfonic acids,sulfuric acid, nitric acid and hydrohalic acids, e.g., hydrochloric acidand hydrobromic acid, and phosphoric acids, e.g., orthophosphoric acid.Other acids can be employed to produce other acid addition salts forisolation, identification or characterizing purposes.

Free acid compounds of Formula (R =H) can be converted into one of thephysiologically acceptable metallic or ammonium salts thereof byreaction with a metal base or amine, respectively. Suitable salts are,for example, the sodium, potassium, magnesium, calcium, and ammoniumsalts, substituted ammonium salts, e.g., the dimethyland diethylammoniumand other dialkylammonium, monoethanol-, diethanol-, andtriethanolammonium, cyclohexylammonium, dicyclohexylammonium anddibenzylethylenediammonium salts.

Conversely, compounds of Formula I can be liberated from the acidaddition salts thereof by treatment with a strong base, e.g., sodium orpotassium hydroxide, sodium or potassium carbonate or a basic ionexchanger, or they can be liberated from the metallic and ammonium saltsthereof by treatment with acids, especially mineral acids, such ashydrochloric acid or sulfuric acid.

When the compounds of Formula I contain a center of asymmetry, they areordinarily present in racemic form. The racemates can be separated intothe optical antipodes thereof by known methods, as disclosed in theliterature, preferably employing chemical methods. In accordancetherewith, diastereomers are formed, for example, from the racemicmixture by reaction with an optically active auxiliary agent. Thus,optionally, an optically active base can be reacted with the carboxylgroup, or an optically active acid can be reacted with the amino groupof a compound of Formula I. For example, diastereomeric salts of thecompounds of Formula I (R =H) can be formed with optically activeamines, e.g., quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindamine, morphine, 1 phenylethylamine, 1 naphthylethylamine,phenyloxynaphthylmethylamine, quinidine and strychnine, basic aminoacids, e.g., lysine, arginine, amino acid esters, and diastereomericsalts of the compounds of Formula I with a basic N-atom can be formedwith optically active acids, e.g., and (-)-tartaric acid, dibenzoyland-()-tartaric acid, diacetyl-(-|-)- and tartaric acid, camphoric acid,p-camphorsulfonic acid, and (-)-mandelic acid, and (-)-malic acid, and()-2-phenylbutyric acid, and (--)-dinitrodiphenic acid and and ()-lacticacid. In a similar manner, ester diastereomers can be produced byesterification of the compounds of Formula I (R =H) with opticallyactive alcohols, e.g., borneol, menthol and 2-octanol. The difference inthe solubility of the thus-obtained diastereomeric salts and/or estersmakes it possible to conduct the selective crystallization of one of theforms and the regeneration of the respective optically active compoundsfrom the mixture.

The racemates can also be separated by chromatographic methods. It ispossible to employ optically active substrate materials, e.g., tartaricacid, amylose, cane sugar, cellulose and acetylated cellulose andoptically inactive and/or optically active mobile phases for theseparation into the pure enantiomers. Also, an optically inactivesubstrate material, e.g., silica gel or aluminum oxide can be used incombination with an optically active mobile phase. The optical antipodescan also be separated biochemically employing selective ensymaticreactions. Thus, the racemic acids of Formula I (-R =H) can be exposedto an asymmetrical oxidase or optionally decarboxylase, which destroysone form by oxidation or decarboxylation, leaving the other formunaltered. A hydrolase can also be used in case of a functional acidderivative of the racemic mixture for the preferred formation of oneoptically active form. Thus, esters of Formula I wherein R is alkyl of1-10 carbon atoms can be subjected to the effect of a hydrolase whichselectively saponifies one of the enantiomers and leaves the otherunchanged.

It is, of course, possible to obtain optically active compounds inaccordance with the described methods for producing the racemic forms byemploying starting substances which are already optically active.

The novel compounds of Formula I and the physiologically acceptable acidaddition salts thereof can be employed in human or veterinary medicinein a mixture with conventional solid, liquid or semiliquid excipients.Useful pharmaceutically acceptable carrier substances are those organicor inorganic materials which are suitable for parenteral, enteral, ortopical application and which do not react adversely with the novelcompounds, such as, for example, water, vegetable oils, benzyl alcohols,polyethylene glycols, gelatin, lactose, starch, magnesium stearate,talc, petroleum jelly, cholesterol, etc. For parenteral application,especially suitable are solutions, preferably oily or aqueous solutions,as well as suspensions, emulsions, or implants. For enteral application,there can also be employed tablets, drages, capsules, syrups, elixirs orsuppositories. For topical application, ointments, salves, creams,powders and liquid and solid aerosols can be employed. Theaforementioned preparations can optionally be sterilized or mixed withauxiliary agents, e.g., preservatives, stabilizers and wetting agents,salts for influencing osmotic pressure, buffers, coloring agents,flavoring agents and/ or aromatic substances.

The compounds of this invention are preferably administered in a dosageof -1000 mg. per dosage unit.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the following examples, the temperatures are set forth in degreescentigrade.

Example 1 (a) 17.7 g. of 4-pyrrolidinophenol(l-p-hydroxyphenylpyrrolidine; obtainable by reacting p-anisidine with1,4- dibromobutane and subsequent treatment of the thusobtained4-pyrrolidinoanisole with HBr) is refluxed with 2.3 g. of sodium and19.5 g. of ethyl 2-bromoisobutyrate in 100 ml. of absolute ethanol for 3hours. The reaction mixture is concentrated by evaporation; the residueis mixed with water, and the aqueous solution is extracted with ether.The ether solution is washed twice with dilute NaOH and twice with waterand then dried. The ether is removed by evaporation, thus obtaining theethyl ester of 2 methyl 2-(4-pyrrolidinophenoxy)-propionic acid, B.P.l65-170/0.05 mm.

10 In place of ethyl 2-bromoisobutyrate, it is also possible to utilizeethyl 2-chloroisobutyrate or ethyl 2-iodoisobutyrate.

Analogously, using the following starting compounds:

4-piperidino-phenol 2-methyl-4-piperidino-phenol (M.P. 231-233";obtainable by the catalytic hydrogenation of 2-chloromethyl-4-nitroanisole to 2-methyl-4-aminoanisole, ether splitting with 48% HBr,and reaction with 1,5-dibromopentane) 2-chloro-4-piperidino-phenol [M.P.-92; obtainable by reacting 2-chloro-4-aminoanisole with1,5-dibromopentane to 2-chloro-4-piperidinoanisole (M.P. 68-6-9) andether splitting with HBr] 3-chloro-4-piperidino-phenol (M.P. 89;obtainable by reacting 3-nitro-4-bromoanisole with piperidine to3-nitro- 4-piperidinoanisole, hydrogenation to 3 amino 4-piperidinoanisole, diazotization and Sandmeyer reaction to3-chloro-4-piperidinoanisole and ether splitting with HBr)4-(3-hydroxypyrrolidino)-phenol [M.P. l63-l64; obtainable by reactingp-anisidine with 1,4-dibromo-2-butanol to4-(3-hydroxypyrrolidino)-anisole (M.P. 73-74) and ether splitting withHBr] 4-(3-hydroxypiperidino)-phenol [M.P. -143"; obtainable byhydrogenation of 3-chloro-4-(3-hydroxypiperidino)-anisole on 5% Pd/MgOto 4-(3-hydroxypiperidino)-anisole (M.P. -172) and ether splitting withHBr] 3-chloro-4-(3-hydroxypiperidino)-phenol [obtainable by reacting3-nitro-4-bromoanisole with 3-hydroxypiperidine to3-nitro-4-(3-hydroxypiperidino)-anisole, hydrogenation on 5% Pd/C to3-amino-4-(3-hydroxypiperidino)-anisole (M.P. 122-123), diazotizationand Sandmeyer reaction to 3-chloro-4-(3-hydroxypiperidino)-anisole (M.P.70-72"), and ether splitting with HBr] 4-isoindolino-phenol (M.P. 21S";obtainable by reacting p-anisidine with o-xylylene dibromide toZ-p-methoxyphenyl isoindoline and ether splitting with HBr)4-(5,6-dimethoxy-isoindolino)-phenol [obtainable by reacting4,5-dimethoxy-1,2-xylylene dichloride (M.P. 83) with p-aminophenylacetate and subsequent alkaline saponification]4-(5,6-methylenedioxy-isoindolino)-phenol [obtainable by reacting4,S-methylenedioxy-l,2-xylylene dibromide (M.P. 96) with p-aminophenylacetate and subsequent alkaline saponification]4-(l,2,3,4-tetrahydroquinolino)-phenol [M.P. l06-108; obtainable byreacting N-p-methoxyphenylanthranilic acid with acetic anhydride andsubsequent saponification to l-p-methoxyphenyl-4-hydroxy-2-quinolone,reaction with POCl to 1-p-methoxyphenyl-4-chloro-2- quinolone (M.P.192-l94) hydrogenation to l-pmethoxyphenyl-3,4-dihydro-2-quinolone (M.P.16l- 162), LiAlH reduction to 1-p-methoxyphenyl-1,2,3,4-tetrahydroquinoline, and ether splitting with HBr]4-(1,2,3,4-tetrahydro-4-quinolyl)-phenol [M.P. 123-125 hydrochloride,M.P. 217-220; obtainable by cyclization of p-methoxycinnamic acidanilide with polyphosphoric acid to4-(p-methoxyphenyl)-l,2,3,4-tetrahydro- 2-quinolone, reduction withLiAlH, to 4-(p-methoxy phenyl)-l,2,3,4-tetrahydroquinoline (M.P. 83-85),and ether splitting with HBr] 4-( l-methyll,2,3,4-tetrahydro-4-quinolyl)phenol [M.P.

220-222; obtainable by methylating4-(p-methoxyphenyl)-1,2,3,4-tetrahydroquinoline with formaldehyde/H /5%Pd/C to 1-methyl-4-p-methoxyphenyl- 1,2,3,4-tetrahydroquinoline (B.P.l64-172/0.0lmm.), and ether splitting with HBr]4-(2-methyl-l-benzimidazolyl)-phenol [M.P. 227-229;

obtainable by treatment of l-(p-methoxyphenyl)-2- methyl-benzimidazole(M.P. 106-108") with HBr] 4-(1-pyrryl) -phenol (M.P. 118-1 19;obtainable by reacting p-aminophenol with 2,S-diethoxytetrahydrofuran)4-(l-benzotriazolyl)-phenol [M.P. l73-175; obtainable by ether splittingof l-(4-methoxyphenyl)-benzotriazole (M.P. 9193) with HBr]4-(2-indanyl)-phenol [M.P. 75-77 obtainable by reacting4-methoxyphenylacetic acid ethyl ester with benzyl chloride to the ethylester of a-benzyl-p-methoxyphenylacetic acid (B.P. 142-145/0.01 mm.),saponification to the acid (M.P. 101-103"), converting the acid withSOCI into the chloride (M.P. 61-62), cyclization toZ-p-methoxyphenyl-l-indanone (M.P. 75-78), NaBH reduction to2-p-methoxyphenyl-l-indanol, dehydration with p-toluenesulfonic acid inbenzene to 2-p-methoxyphenyl-indene, catalytic hydrogenation toZ-p-methoxyphenyl-indane, and ether splitting with HBr]4-(4-piperidinophenyl)-phen0l [M.P. 193-195; obtainable by reacting4-amino-4'-methoxy-biphenyl with 1,5- dibromopentane to4-piperidino-4-methoxy-biphenyl (M.P. 190-192"), and ether splittingwith HBr],

the following compounds are obtained by reaction with ethyl2-bromoisobutylrate (reaction times are set forth in parentheses) orwith ethyl 2-chloroisobutyrate or ethyl 2-iodoisobutyrate, respectively:

ethyl ester of 2-methyl-2-(4-piperidinophenoxy)-propionic acid (3hours), B.P. 158/ 0.2 mm.;

ethyl ester of 2-methyl-2-(2-methyl-4-piperidinophenoxy propionic acid(3 hours), B.P. 161167/ 0.05 mm.; hydrochloride, M.P. 185-187";

ethyl ester of 2-methyl-2-(2-chloro-4-piperidinophenoxy)- propionic acid(2 hours), B.P. 171-l75/0.01 mm.;

ethyl ester of 2-methyl-2-(3-chloro-4-piperidinophenoxy)- propionic acid(2.5 hours), B.P. 138/0.05 mm.;

ethyl ester of 2-methyl-2- [4-(3-hydroxypyrrolidino phenoxy]-propionicacid (6 hours), B.P. 156-157 0.01 mm.;

ethyl ester of 2-methyl-2-[4-(3-hydroxypiperidino)-phenoxy]-propionicacid hours), B.P. 200-206/ 0.05 mm.;

ethyl ester of2-methyl-2-[3-chloro-4-(3-hydroxypiperidino)-phenoxy]-propionic acid 15hours), oily;

ethyl ester of 2-methyl-2-(4-isoindolinophenoxy)-propionic acid (5hours), M.P. 70-7l;

ethyl ester of 2-methyl-2-[4-(5,6-dimethoxy-isoindolino)-phenoxy]-propionic acid (5 hours), M.P. 139141;

ethyl ester of 2-methyl-2- [4- (5,6-methylenedioxyisoindolino)-phenoxy]-propionic acid (5 hours), M.P.137-13 8 ethyl ester of2-methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid (3hours), B.P. 178/ 0.01 mm.;

ethyl ester of 2-methyl-2-[4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionic acid (48 hours), M.P. 64-66;

ethyl ester of2-methyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionicacid hours), B.P. l91l97/0.05 mm.;

ethyl ester of 2-methyl-2- [4-(2-methyl-1-benzirnidazolyl)phenoxy]-propionic acid (15 hours), M.P. 93-94";

ethyl ester of 2-methyl-2-[4-(1-pyrryl)-phenoxy]- propionic acid (15hours), M.P. 43-44;

ethyl ester of 2-methyl-2-[4-(1-benzotriaz0lyl)-phen0xy]- propionic acid(15 hours), oily;

ethyl ester of 2-methyl-2- [4- (Z-indanyl) -phenoxy] propionic acid (12hours), B.P. 162-164/0.01 mm.;

ethyl ester of 2-methyl-2-[4-(4-piperidinophenyl)- phenoxy]-propionicacid, M.P. 100-102.

(b) 13.5 g. of the ethyl ester of2-methyl-2-(4-pyrrolidinophenoxy)-propionic acid is refluxed with 6.25g. of KOH in 80 ml. of ethanol for 2 /2 hours. The mixture is thenconcentrated by evaporation, mixed with water, extracted with ether, andhydrochloric acid is added thereto, up to a pH of 5. The thus-obtained2-methyl-2- (4-pyrrolidinophenoxy)-propionic acid is filtered andrecrystallized from ethanol; M.P. 105-107".

Analogously, the following compounds are produced by saponification ofthe corresponding ethyl esters (acidification to the indicated pHvalues):

2-methyl-2-(4-piperidinophenoxy) -propionic acid (pH 5), M.P. 202-204;

2-methyl-2-(2-methyl-4-piperidinophenoxy)-propionic acid (pH 5), M.P.178-179";

2-methyl-2-(2-chloro-4-piperidinophenoxy)-propionic acid (pH 5), M.P.162-163;

2-methyl-2- (3-ch10ro-4-piperidinophenoxy)-propionic acid (pH 5), M.P.97-98";

2-methyl-2-[4-(3-hydroxypyrrolidino)-phenoxy]- propionic acid (pH 4.5)M.P. 130-131";

2-methyl-2-[4-(3-hydroxypiperidino)-phenoxy]- propionic acid (pH 4.5),M.P. 158-160;

2-methyl-2-[3-chloro-4-(3-hydroxypiperidino)-phenoxy]- propionic acid(pH 4), M.P. 115-117;

2-rnethyl-2-(4-isoind0linophenoxy)-propionic acid (during thesaponification, the K-salt precipitates, which is filtered off anddecomposed with hydrochloric acid), M.P. 202;

2-methyl-2- [4- 5 ,6-dimethoxy-isoindolino) -phenoxy] propionic acid;

2-methyl-2- [4- 5 ,6-methylenedioxy-isoindolino phenoxy1-propionic acid;

2-methyl-2- [4-( 1,2,3 ,4-tetrahydroquinolino) -phenoxy] propionic acid(pH 4), M.P. 115-117";

2-methy1-2- [4-( 1,2,3,4-tetrahydro-4-quinolyl) -phenoxy1- propionicacid (pH 5.5), cyclohexylamine salt, M.P. 221-224;

2-methyl-2- [4-( 1-methyl-1,2,3,4-tctrahydr0-4-quino1yl)phenoxy]-propionic acid (pH 4), cyclohexylamine salt, M.P. 221-223;

2-methyl-2- [4- (2-methyll-benzimidazolyl)-phenoxy] propionic acid (pH5), M.P. 125-127";

2-methyl-2- [4-( l-pyrryl)-phenoxy]-propionic acid (pH 2-methyl-2- [4-l-benzotriazolyl) -phenoxy] -propionic acid (pH 5), M.P. 73-75;

2-methyl-2-[4-(2-indanyl)-phenoxy]-propionic acid (pH 3), M.P. 125-127;

2-methyl-2- [4- (4-piperidinophenyl) -phenoxy] -propionic acid (pH 5),M.P. ZZZ-224.

Example 2 13 g. of 4-( l,2,3,4-tetrahydroquinolino)-phenol is added to asuspension of 1.45 g. of NaH in 100 ml. of dimethylacetamide. Thereaction mixture is agitated for one hour at room temperature, and then11.8 g. of ethyl a-bromoisobutyrate is added thereto and the mixturemaintained at for 20 hours. Thereafter, the reaction mixture is cooled,mixed with water, and extracted with ether. The ether solution is washedtwice with 2 N NaOH and concentrated to dryness by evaporation afterdrying, thus obtaining the ethyl ester of2-methyl-2-[4-(l,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid,B.P. 178/ 0.01 mm.

Example 3 A mixture of 4.5 g. of 4-(1,2,3,4-tetrahydroquinolino)- phenoland 0.46 g. of sodium in ml. of xylene is refluxed for 3 hours and thenallowed to cool to 20. To this reaction mixture is added 4.2 g. of ethyl2-bromoisobutyrate in 10 ml. of xylene, the suspension agitated underboiling for 6 hours, cooled, and treated with 2 ml. of ethanol. Theinorganic precipitate is filtered off, the filtrate is evaporated, theresidue taken up in ether, the solution washed with NaHCO solution andsaturated NaCl solution, dried over MgSO and concentrated byevaporation. Ihe product thus obtained is the ethyl ester of 2 methyl2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]- propionic acid, B.P. 178/0.01 mm.

Analogously, by reaction with the following compounds:

methyl ester of 2-bromoisobutyric acid n-propyl ester of2-bromoisobutyric acid isopropyl ester of 2-bromoisobutyric acid n-butylester of 2-bromoisobutyric acid isobutyl ester of 2-bromoisobutyric acidsec.-butyl ester of 2-bromoisobutyric acid tert.+butyl ester of2-brornoisobutyric acid isoamyl ester of 2-bromoisobutyric acid n-hexylester of 2-bromoisobutyric acid (2-ethylhexyl) ester of2-bromoisobutyric acid n-decyl ester of Z-bromoisobutyric acid,

the corresponding esters of the acids set forth in Example 1(b) areobtained from the phenols disclosed in Example 1, for example the methylester of 2-methyl-2-[4-(1,2,3,4- tetrahydroquinolino)-phenoxy]-propionicacid, MP. 64-- 65, or the n-propyl ester (B.P. 190-200/ 0.01 mm),isopropyl ester, n-butyl ester, isobutyl ester, sec.-butyl ester,tert.-butyl ester, isoamyl ester, n-hexyl ester, (Z-ethylhexyl) ester,or n-decyl ester thereof.

Example 4 A solution of 19.5 g. of the ethyl ester of 2-bromoisobutyricacid in 30 ml. of acetone is gradually added to an agitated mixture of22.5 g. of 4-(1,2,3,4-tetrahydroquinolino)-phenol, 13.8 g. of K and 80ml. of acetone. The mixture is refluxed under stirring for 12 hours,filtered, evaporated, distilled, and the product thus obtained is theethyl ester of 2-methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid, B.P. 178/0.01mm.

Example 5 g. of sulfuric acid is added to a mixture of 12 g. of4-(1,2,3,-4-tetrahydroquinolino)-phenol and 15 g. of ethylZ-hydroxybutyrate, and the reaction mixture is agitated for 2 hours at5060. After cooling, the mixture is mixed with water; dilute NaOH isadded up to a. pH of 8, and the aqueousphase is extracted with ether.The mixture is dried, concentrated byevaporation, and the ethyl ester of2 methyl-2-[4- (1,2,3,4-tetrahydroquinolino)-phenoxy]- propionic acid isthus obtained, B.P. 178/ 0.01 mm.

Example 6 (a) 22.5 g. of 4-(1,2,3,4-tetrahydroquinolino)-phenol isdissolved in 200 ml. of acetone. Under agitation, 4 g. of NaOH is addedthereto, and then, under stirring and refluxing, 16.7 g. of2-bromoisobutyric acid (or 12.25 g. of 2-chloroisobutyric acid) in 60ml. of acetone is added dropwise thereto; the mixture is stirred foranother hour at 56 and allowed to stand for 24 hours. The acetone isdistilled off, the residue dissolved in 1 l. of water, the solutionwashed several times with ether, and acidified to a pH of 4 with HCl.The thus-precipitated 2-methyl-2-[4-(1,2,3,4-tetrahydroqumolino)-phenoxy]-propionic acid is filtered andrecrystallized from ethanol or from diisopropyl ether/petroleum ether,M.P. 115-117.

Analogously, the acids set forth in Example 1(b) are obtained from thephenols disclosed in Example 1(a).

(b) One gram of 2methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid isdissolved in ml. of ether and mixed dropwise with ethereal CH N solutionuntil the yellow coloring thus obtained is permanent. Afterconcentrating by evaporation, the methyl ester of Z-methyl [4(1,2,3,4-tetrahydroquinolino)-phenoxy]- propionic acid is obtained, M.P.64-65"; B.P. 195 0.15 mm.

(c) 5 g. of 2methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid isdissolved in 200 ml. of saturated ethanolic hydrochloric acid; themixture is allowed to stand for 12 hours at room temperature, is thenrefluxed for 2 hours, and concentrated by evaporation. The residue isdissolved in water, the aqueous solution adjusted to a pH of 8 with 1 NNaOH, and extracted with ethyl acetate. The mixture is dried,concentrated by evaporation, and the ethyl ester of 2methyl-2-[4-(1,2,3,4- tetrahydroquinolino)-phenoxy]-propionic acid isthus produced, B.P. 178/0.01 mrn.

Analogously, the corresponding ethyl esters listed in Example 1(a) areobtained from the acids set forth in Example 1(b) with ethanolichydrochloric acid.

Example 7 23 g. of 1,4-dibromo-2-butanol, 22 g. of the ethyl ester of 2methyl 2 (4 an1inophenoxy)-propionic acid, and 27 g. of K CO arerefluxed in 400 ml. of n-butanol for 12 hours. Thereafter, the solventis distilled otf, the residue mixed with water, and extracted with ethylacetate. The extract is dried and evaporated, thus obtaining the ethylester of 2-methyl-2- [4(3-hydroxypyrrolidino)-phenoxy]- propionic acid,B.P'. 156l57/ 0.01 mm.

Analogously, by reaction of the following compounds:

methyl ester of 2-methyl-2-(4-aminophenoxy)-propionic acid (obtainableby al-kylation of Na-4nitrophenolate with methyl 2-bromoisobutyrate tothe methyl ester of 2-methyl-2-(4-nitrophenoxy)-propionic acid andsubsequent hydrogenation),

methyl ester of 2-methyl-2-(2-methyl-4-aminophenoxy)- propionic acid,

methyl ester of 2-methyl-2-(2-chloro-4-aminophenoxy)- propionic acid,

methyl ester of 2-methyl-2-(3-chloro-4-aminophenoxy)- propionic acid,

the following compounds are produced with 1,4-dibromobutane,1,5-dibromopentane, 1,4-dibromo-2-butanol, 1,5- dibromo-2-pentanol,o-xylylene bromide, 3,4-dimethoxy- 1,2-xylylene bromide or3,4-methylenedioxy-1,2-xylylene bromide, respectively:

methyl ester of 2-methyl-2-(4-pyrrolidinophenoxy)- propionic acid methylester of 2-methyl-2-(4-piperidinophenoxy)- propionic acid methyl esterof 2-methyl-2- (2-methyl-4-piperidinophenoxy)-propionic acid methylester of 2rmethyl-2-(2-chloro-4-piperidinophenoxy)-propionic acid methylester of 2-methyl-2-(3-chloro-4-piperidinophenoxy)-propionic acid methylester of 2-methyl-2- [4-(3-hydroxypyrrolidino)- phenoxy]-propionic acidmethyl ester of 2-methyl-2- [4- (3-hydroxypiperidino)-phenoxy]-propiom'c acid methyl ester of2-methyl-2-[3-chloro-4-(3-hydroxypiperidino)-phenoxy]-propionic acidmethyl ester of 2-methyl-2-(4-isoindolinophenoxy)- propionic acid methylester of 2-methyl-2- [4-(5,6-dimethoxy-isoindolino)-phenoxy]-propionicacid methyl ester of2-methyl-2-[4-(5,6-methylenedioxy-isoindolino)-phenoxy]-propionic acid.

Example 8 A mixture of 25.1 g. of the isobutyl ester of 2-methyl-2-(4-aminophenoxy)-propionic acid, 21.6 g. of 1,4-dibromobutane, 14 g.of Na 'CO and m1. of acetonitrile is refluxed under agitation for 48hours. The mixture is then filtered, concentrated by evaporation, theresidue taken up in dilute hydrochloric acid, washed with ether,rendered alkaline with dilute solution of sodium hydroxide, extractedwith ether, dried, evaporated, and the compound thus obtained is theisobutyl ester of 2-methyl- 2-(4-pyrrolidinophenoxy)-propionic acid,B.P. 180-190/ 0.02 mm.

Example 9 17 g. of the ethyl ester of2-methyl-2-(4-aminophenoxy)-propionic acid is refluxed in 170 m1. ofn-butanol together with 32.4 g. of 1,4-dibromobutane and 11 g. ofpulverized K CO for 15 hours. The mixture is then cooled, filtered, thebutanol is distilled E, the residue dissolved in 150 ml. of benzene, andthe solution boiled for 2 hours with ml. of acetic anhydride. Thereaction mixture is cooled, washed with 1 N NaOH, and extracted with 20%strength HCl. The aqueous hydrochloric acid solution is made alkaline,extracted with ether, the ether phase washed neutral with water, dried,and evaporated, thus obtaining the ethyl ester ofZ-methyl-2-(4-pyrrolidinophenoxy)-propionic acid, B.P. 165- 170/0.05 mm.

Example 10 At 40-50, 12 g. of chloroform is added dropwise to a mixtureof 9 g. of 4*(1,2,3,4-tetrahydroquinolino)- phenol, 30 g. of acetone,and 8.4 g. of pulverized KOH. The mixture is refluxed for 12 hours,evaporated, the residue mixed with water, extracted with ether,acidified with dilute hydrochloric acid to a pH of 5, and extracted withether. The ether solution is extracted with dilute solution of sodiumcarbonate, the latter washed with ether, then again acidified, and againextracted with ether. The ether extracts are dried with sodium sulfateand concentrated by evaporation, thus obtaining 2-methyl-2-[4- (1,2,3,4tetrahydroquinolino)phenoxy]-propionic acid, M.P. 115-117".

Analogously, with acetone/chloroform/KOH, the acids set forth in Example1(b) are obtained from the phenols listed in Example 1(a).

In an analogous manner, using the following starting compounds:

3-methyl-4- 1,2,3,4-tetrahydroquinolino) -phenol 3-ethyl-4-( 1,2,3,4-tetrahydroquinolino) -phenol 3-n-butyl-4-(1,2,3,4-tetrahydroquinolino -pheno13-fluoro-4-(1,2,3,4-tetrahydroquinolino)-phenol 3-chloro-4-(1,2,3,4-tetrahydroquinolino) -pheno1 3-bromo4-1,2,3,4-tetrahydroquinolino) -phenol 3-iodo-4-(l,2,3,4-tetrahydroquinolino) -phenol 4- S-methyl-isoindolino -phenol 4-(S-n-butyl-isoindolino) -phenol 4- S-methoxy-isoindolino) -phcnol 4-S-n-butoxy-isoindolino -pheno1 4-(5-fluoro-isoindolino) -phenol 4-S-chloro-isoindolino -phen01 4- (5 -bromo-isoindolino) -phenol 4-(5-iodo-isoindolino -pheno1 4- (4,7-dimethoxy-isoindolino -phenol thefollowing compounds are produced with acetone/ chloroform/KOH:

2-methy1-2- [3-methyl-4-( 1,2,3,4-tetrahydroquinolino)phenoxy]-propionic acid 2-rnethyl-2- [3-ethy1-4-(1,2,3,4-tetrahydroquinolino)- phenoxy]-propionic acid 2-methyl-2-3-n-butyl-4-( 1,2,3,4-tetrahydroquinolino)- phenoxy]-propionic acid2-methyl-2- 3-fiuoro4-( 1,2,3,4-tetrahydroquinolino) phenoxy]-propionicacid 2-methyl-2-[3-chloro-4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid 2-methyl-2- [3-bromo-4-1,2,3,4-tetrahydroquinolino)- phenoxy]-propionic acid 2-methyl-2-3-iodo-4-( 1,2,3,4-tetrahydroquinolino phenoxy]-propionic acid2-methyl-2- [4- S-methyl-isoindolino) -phenoxy] propionic acid2-methyl-2- [4- S-n-butyl-isoindolino) -phenoxy] propionic acid 162-methyl-2-[4-(S-methoxy-isoindolino)-phenoxy]- propionic acid2-methyl-2- [4- S-n-butoxy-isoindolino -phenoxy]- propionic acid2-methyl-2- [4- S-fluoro-isoindolino -phenoxy]- propionic acid2-methyl-2-[4-(5-chloro-isoindolino)-phenoxy]- propionic acid2-methyl-2- [4-(S-bromo-isoindolino)-phenoxy]- propionic acid2-methyl-2-[4-(S-iodo-isoindolino)-phenoxy]- propionic acid 2-methyl-2-[4 (4,7-dimethoxy-isoindolino) -phenoxy] propionic acid.

Example 11 2 g. of 2-methy1-2-(4-pyrrolidinophen0xy)-propionitrile(obtainable from 4-pyrr0lidino-phenol and 2- bromoisobutyronitrile) isrefluxed with 2 g. of KOH in 20 ml. of ethanol and 2 ml. of water for 40hours. The mixture is then concentrated by evaporation, mixed withwater, extracted with ether, and hydrochloric acid is added thereto, upto a pH of 5, thus obtaining 2-methyl-2-(4-pyrrolidinophenoxy)-propionic acid, M.P. l07.

Analogously, the corresponding carboxylic acids are produced by alkalinehydrolysis of the following compounds:

2-methyl-2- (4-piperidinophenoxy -propionitrile 2-methyl-2-2-methyl-4-pip eridinophenoxy) propionitrile 2-methy1-2-2-chloro-4-piperidinophenoxy) pro pionitrile 2-methy1-2-3-chloro-4-piperidinophenoxy)- pro pionitrile 2-methyl-2- [4-3-hydroxypyrrolidino) -phenoxy]- propionitrile 2-methyl-2- [4-(3-hydroxypiperidino) -phenoxy]- propionitrile 2-methyl-2-[3-chloro-4-(3-hydroxypiperidino phenoxy] -propionitrile 2-methyl-2-4-isoindolinophenoxy) -propionitrile 2-methyl-2- [4-5,6-dimethoxy-isoindolino -phenoxy]- propionitrile 2-methyl-2- [4-5,6-methylenedioxy-isoindolino phenoxy] -propionitrile2-methyl-2-[4-(1,2,3,4-tetrahydroquinolino)- phenoxy] -propionitrile2-methyl-2- [4-( 1,2,3,4-tetrahydro-4-quinolyl) phenoxy] -propionitrile2-methyl-2-[4-(1-methyl-1,2,3 ,4-tetrahydro-4- quinolyl -phenoxy]-propionitrile 2-methyl-2- [4-(2-methyl-1-benzimidazo1yl)- phenoxy]-propionitrile 2-rnethyl-2- [4- l-pyrryl -phenoxy] -propionitrile2-methyl-2- [4- l-benzotriazolyl)-phenoxy] propionitrile 2-methy1-2- [4-(Z-indanyl) -phen0xy] -propionitrile 2-methyl-2- [4- (4-piperidinophenyl) -phenoxy] propionitrile.

Example 12 14 g. of 2-methyl-2-(4-pyrrolidinophenoxy)-propionitrile isrefluxed with 60 ml. of acetic acid and 60 ml. of concentratedhydrochloric acid for 2 hours under a nitrogen atmosphere. The mixtureis evaporated, dissolved in dilute NaOH, extracted with ether, andhydrochloric acid is added to a pH of 5, thus obtaining2-methyl-2-(4-pyrro- 1idinophenoxy)-propionic acid, M.P. 105-107.

Analogously, the corresponding carboxylic acids are produced by anacidic hydrolysis of the nitriles set forth in Example 11.

Example 13 3 g. of 2 methyl-2-(4-pyrrolidinophenoxy)propionic acid amide(obtainable from 4-pyrrolidinophenol and 2- bromoisobutyramide) and 5 g.of KOH are refluxed in 100 ml. of ethanol under a nitrogen atmospherefor 3 hours. The mixture is then concentrated by evaporation, mixed withWater, extracted with ether, and hydrochloric acid is added thereto, upto a pH of 4, thus producing 2- methyl 2(4-pyrrolidinophenoxy)-propionic acid, M.P. 105-107.

Analogously, the corresponding carboxylic acids are obtained by alkalinehydrolysis of the following compounds:

2-methyl-2-(4-piperidinophenoxy)-propionic acid amide2-methyl-2-(Z-methyl-4-piperidinophenoxy)-propionic acid amide2-methyl-2-(2-chl0ro-4-piperidinophenoxy)-propionic acid amide2-methyl-2-(3-chloro-4-piperidinophenoxy)-propionic acid amide2-1nethyl-2- [4- (3 -hydroxypyrrolidino -phenoxy] propionic acid amide2-Inethyl-2- [4- S-hydroxypiperidino -phenoxy] propionic acid amide2methyl-2- [3 -chloro-4- (3 -hydroxypiperidino -phenoxy] propionic acidamide 2-methyl-2-(4-isoindolinophenoxy)-propionic acid amide2-methyl-2-[4-(5,6-dimethoxy-isoindolino)-phenoxy]- propionic acid amide2-methyl-2-[4-(5,6-methylenedioxy-isoindolino)- phenoxy]-propionic acidamide 2-methyl-2- [4-( 1,2,3,4-tetrahydroquinolino -phenoxy] propionicacid amide 2-methyl-2- [4- 1,2,3,4-tetrahydro-4-quinolyl) -phenoxy]propionic acid amide 2-methyl-2- [4-l-methyl-1,2,3,4-tetrahydro-4-quinolyl)- phenoxy]-propionic acid amide2-methyl-2- [4- (Z-methyll-benzimid azolyl -phenoxy] propionic acidamide 2-methyl-2-[4-(1-pyrryl)-phenoxy]-propionic acid amide 2-methyl-2-[4-( l-benzotriazolyl -phenoxy] -propionic acid amide 2-methyl-2-[4-(Z-indanyl)-phenoxy]-propionic acid amide 2-methyl-2- [4-4-piperidinophenyl -phenoxy] -propionic acid amide.

Example 14 g. of 2 methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy1-propionyl chloride (obtainable from the acid and SOCI is heatedwith 100 ml. of absolute n-propanol to 95 for 3 hours. The mixture isthen concentrated by evaporation, the residue mixed with dilute sodiumhydroxide solution, and the aqueous solution is extracted with ether.The ether solution is washed twice with dilute NaOH and twice withwater, dried, and the ether is removed by evaporation, thus obtainingthe n-propyl ester of 2-methyl-2- [4- 1,2,3,4-tetrahydroquinolino-phenoxy] propionic acid, B.P. 190-200/0.01 mm.

In an analogous manner, the corresponding esters are produced byalcoholysis of the acid chlorides of Formula V (W=COC1).

Example 15 9 g. of 2 methyl-2'[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionyl chloride is dissolved in 100 ml. of absolutetetrahydrofuran and mixed with 3 g. of potassium tert.-butylate. Themixture is agitated at room temperature for minutes, filtered, thefiltrate concentrated by evaporation, worked up as described in Example14, and the 18 tert.-butyl ester of 2 methyl2-[4-(l,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid is thusproduced, B.P. -185/0.01 mm.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

1. A compound of the formula wherein R is H or alkyl of 1-10 carbonatoms, R is H, alkyl of 1-4 carbon atoms or halogen; or physiologicallyacceptable salt thereof.

2. A compound of claim 1, 2 methyl-2-[4-(1,2,3,4-tetrahydroquinolino)-phenoxy]-propionic acid.

3. A compound of the formula R2 RI W-o-ownm-ooom wherein R is H or alkylof 1-10 carbon atoms, R is H, alkyl of 1-4 carbon atoms or halogen, R isH or alkyl of 1-10 carbon atoms; or a physiologically acceptable saltthereof.

4. A compound of claim 3, 2 methyl-2-[4-(1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionic acid.

5. A compound of claim 3, 2 methyl-2-[4-(1,2,3,4- tetrahydro 4 Fquinolyl)-phenoxy]-propionic acid ethyl ester.

6. A compound of claim 3, 2 methyl-2-[4-(l-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionic acid.

References Cited UNITED STATES PATENTS 2,394,916 2/ 1946 Jones 260-5513,397,055 8/1968 Weil 7l--100 3,563,998 2/1971 Ariot 260-295 R 3,681,3658/1972 Ariot 260-268 PH OTHER REFERENCES Dvjovne et al., Chem. Abstr.,vol. 74,. col. 75049; (April 1971).

Nakamura et al., Chem. Abstr. vol. 75, col. 15154519, abstracting SouthAfrica 7005, 223 (March 1971).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-243 B, 293.62, 308 B, 309.2, 326.11, 326.3, 326.5, 471 R, 473 A, 539R, 621 R, 999

